79-LB: Pharmacokinetics and Pharmacodynamics of Avexitide (Exendin 9-39) in Neonates and Infants with Congenital Hyperinsulinism

Abstract

Congenital hyperinsulinism (HI) is an ultra-rare pediatric disease with high unmet medical need. Avexitide, a first-in-class GLP-1 receptor antagonist, has been shown to reduce hyperinsulinemic hypoglycemia in children and adolescents with HI. Among neonates, maintenance of euglycemia often depends on high glucose infusion rates (GIR) by central lines. Those whose GIR exceeds 10 mg/kg/min frequently require subtotal pancreatectomy, leading to prolonged hospitalization, life-threatening complications, and induction of insulin-dependent diabetes. In this Phase 2 trial, 13 neonates and infants ages 11 days to 5 months with diazoxide-unresponsive HI were randomized to single ascending doses of avexitide and placebo by continuous IV infusion for up to 12 hours on two days in crossover design. Plasma glucose was monitored with GIR adjusted to maintain euglycemia. The primary endpoint was GIR. Relationships between avexitide exposure and absolute difference in GIR during avexitide vs. placebo were evaluated. A pharmacokinetic (PK) simulation of avexitide following subcutaneous (SC) injection in neonates was performed based on a modified PopPK model previously established with inclusion of weight-based allometric scaling. Relative to placebo, avexitide significantly reduced GIR when evaluated across dose levels (p=0.0087) with dose-dependent improvements observed. On average, avexitide infused at 100, 200 and 1000 pmol/kg/min demonstrated 1.3 (15%), 2.9 (24%), and 4.3 (56%) mg/kg/min reductions in GIR relative to placebo and entirely abolished glucose requirements in 50% of patients at the top dose. PK/PD analysis demonstrated an exposure-response relationship best described by an Emax model. PK simulation indicated that avexitide dosed by SC injection may achieve adequate steady-state exposure to lower GIR requirements. Subcutaneous avexitide may represent a promising therapeutic approach for treatment of neonates and infants with HI. Disclosure C. Craig: Consultant; Self; Eiger BioPharmaceuticals. D. D. De leon: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Hanmi Pharmaceutical, Heptares Therapeutics, Poxel SA, Soleno Therapeutics, Inc., Employee; Spouse/Partner; Merck & Co., Inc., Research Support; Self; Crinetics Pharmaceuticals, Tiburio, Zealand Pharma A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK083670); Clifford and Katherine Goldsmith Foundation; National Center for Research Resources (UL1RR024134); Eiger BioPharmaceuticals